Preclinical Evaluation Of Her3 Mutations And Rational Combinations With Akt Inhibition In Enhancing Anti-Tumor Activity Of Her3 Inhibition In Gastric Cancer

Molecular activating events involving the ERBB RTK family members (EGFR (ERBB1), HER2 (ERBB2), HER3 (ERBB3), HER4 (ERBB4)) drive oncogenesis by inducing proliferation, invasion and survival primarily through RAS/MAPK and PI3K/AKT signaling pathways in several cancers. The clinical successes of HER2 directed therapies are well known in breast cancer and more recently, in gastric cancer. However, resistance develops invariably and gastric cancer continues to be a largely unmet disease necessitating novel therapeutic interventions. Recent reports have highlighted HER3 as an emerging target as it is frequently overexpressed, mutated, preferentially dimerizes with HER2 to activate signaling and is induced as a result of de novo or acquired resistance to PI3K-AKT, MAPK and RTK pathway inhibitors. We explored the utility of an ADCC and CDC enhanced potent anti-HER3 therapeutic antibody (GSK2849330) as a single agent or in combination with a selective small molecule AKT inhibitor (GSK2110183) in patient-derived xenograft (PDX) models of gastric cancer. A panel of 15 HER3 mutant and 4 HER3 wildtype PDX models was screened in vivo for responses to GSK2849330 as measured by% tumor growth inhibition (%TGI). Several models were characterized for other molecular alterations (e.g. HER2, PTEN, HER3, etc.) and represented various subsets of gastric cancer. As a single agent administered at 25mg/kg IP BIW, GSK2849330 was modestly effective (TGI ≥ 50%) in 2/15 mutant and 2/4 wildtype models. While context is likely to matter to drive dependence on HER3, no obvious predictive markers were observed. Furthermore, we evaluated the effect of combination therapy with an AKT inhibitor (GSK2110183) administered at 60mg/kg PO QD in a HER3 wildtype, PTEN deficient model. This resulted in significant durable tumor growth inhibition (∼94% TGI) with improved survival and noticeable tumor regression in a few mice in the combination treatment group relative to either single agent groups. Tumor samples collected at the end of the study showed pronounced pharmacodynamic modulation of p-AKT and p-HER3, demonstrating on target activity of these agents. Taken together, our findings suggest that modest anti-tumor activity was elicited by GSK2849330 as monotherapy in select gastric PDX models with no clear associations between response and HER3 mutations or other known markers. However, robust durable activity was observed upon combination with GSK2110183. To our knowledge, this is the first in vivo evidence supporting the rational combination of a selective AKT inhibitor (GSK2110183) and an anti-HER3 therapeutic antibody (GSK2849330), both of which are actively undergoing clinical trials and warrant further investigation in gastric cancer. Citation Format: Gopi Ganji, Sherry Qin, Crystal Qin, Neil Clarke, Carolyn Buser-Doepner, Christopher Matheny, Rakesh Kumar, Biju Mangatt. Preclinical evaluation of HER3 mutations and rational combinations with AKT inhibition in enhancing anti-tumor activity of HER3 inhibition in gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1192.